Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
7 ~
Ref. 6510/252
Process for the manufacture of furan derivati
The invention is concerned with a process for the
manufacture of subs~ituted furans; ther~by 4-hydroxy-Z-yn-1-
ones or acetals or kstals thereof are cyclized with nucleophilic
S-compounds to 3-S-furans, whereby this 3-S atorrl can be
eptionally substituted, and the acetylene derivatives, the 4-
hydroxy-2-yn-1-ones, can be optionally 1- and/or 4-alkyl or
alkenyl substituted.
More particularly, ths invention is concerned with a proc~ss
for the manufactlJre of substituted furan dsrivatives of the
formula
c
Rt~R2
wherein R1 and R2 signify hydro~en, Cl 6-alkyl, such as
CH3, C2Hs or C2 6-alkanyl, sueh as propenyl, etc.
and C represents a sulphur-contclinin~ residue.
The process comprises cyclizing an acetylen~ derivative
O OH
R1 C--=1R2 11
or an acetal or ketal theresf using a reagent lll which contains at
least one nucleophilic sulphur atom
AE3 lll
wherein
A= H+, NH4+, N(C1 6-alkyl)3H+, an alkali metal cation, an
alk~line earth metal cation,
B = R4-S-, SCN-, AS203-, H2NC(=S)NH-, R5-S(_o)O-, R5-S-S-,
and
F~4 = H, Cl 6-alkyl, e.g. methyl, sec.butyl,
C2 ~-alkenyl, e.g. propenyl, 2-methyl-butenyl, e~c.,
2 ~ 2
C2 6-alkynyl, e.g. butynyl (1), propynyl (1~, C1 6-alkyl
substituted by halogen (F, Cl, Br, 13, OH, SH, C=O or a C1 6-
carboxylic acid residue or a C1 6-alkylcarboxylic acid
derivative, e.g. -(::H2(cH2)2cooc2Hs~ -C} 12cH(~l J3)CH2(~0C~3
-CH2CH~CH3)SH,
C1 6-acyl, e9 C1 6-alkanoyl~ such as acetyl, butyryl,
substituted (optionally also heterocyclically) ~ 6-acyl,
e.~. 2-tetrahydrofuranylmethylcarbony!,
R5 = Cl 6-allsyl, e.g. CH3, aryl, e.g. phenyl, he~eroaryi,
especially residues of 5-ring compounds, such as furyl or
thiophenyl,
and optionally conver~ing the primary reaction product of the
formula
B
,~
Rl o R~
I'
by a secondary reaction in~o a subsequent product of the formula
S-R
Rl R2
wherein R = R4; or SR5, e.g. S-(:~1 6-alkyl, such as S-CH3, S-
sec.butyl, ~to., S~ 6-alkyl functionalized with haiogen,
hydroxy, SH, carbonyl, carbo)~yl, S-alkyl, such as thio-
phenyl, S-heteroaryl, such as thio-furfuryl, 3-S-thio-furyi,
3-S-thiophenyl,
whereby all (hetero)aryls in the scope of the present
invention can be optionally substituted by R1 an~ R2 and all
hydrocarbon residues c~n be straight-chain or branched.
The procass can be represented schematically as follows:
~çhQ~
OH
R~ 2
13a
B S-R
or ~ AB - ---_ ~ ~~~~~- ~-~~ ~R2
111
I' Il"
F~30 Oi I
3 ~ 2 (b)
Il b
The startin~ ma~erials ll and lll are conveniently brought
together in the ratio of about 2:1 to abou~ 1:5, pr~ferably about
1:1, with the addition of a minoral acicl, such as nitric acid,
phosphoric acid or, pref0rably, sulphurio acid, or an organic acid,
e.g. acetic aoid, citric acid, etc., and an organic solvent, such as
an aliphatic or aromatic, optionally halo~ena~2d hydrocarbon, an
ether, an alcohol, etc., such as pentane, m~thyiene ohloride,
toluene9 die~hyi ether, ~trahydrofuran, MTBE, ethanol, ~tc., and
stirred a~ tempera~ur~s of about 0 to about 100C, preferably
about 20-50C.
Preferably, ll is added dropwise to IIJ and processed at pH
vaiues below about 4. In certain cases it has been observed that
prior base treatm~nt of the mixture of startin~ materials ll + lll
expedites the addition of B in the ,B-position of ll. As bases there
can preferably be us9d in this case tertiary amines, such as e.g.
N(C2Hs)3, diazabicyclooctane, p-diaminopyri~ine, etc. The
suitable temperatures are about 20 to about 50C. This
procedure is indicated especially when AB = R4SH, Rs-S-S-H, etc.
4 '~9~
The reaction of 11 with 111 can be carried out in a one-phase
or two-phase (poiar/apolar) system. The latt~r variant is pref0r-
red. In the case of ~he first variant, the reaction is preferably
carried out in polar solvents, such as alcohols, e.g. etharlol, etc.,
ace~one, acetonitrile, water, etc. or mix~ures of such solvents.
The acetalization or ketalization of 11 is effected in a
manner known per se and ~he meanings of R3 in formula lI(b) are:
R30 011
F330~ - ~R2 (b)
llb
R3 = C1 ~,-alkyl
R3 + R3 + C of llb = 5- or 6-membered ring.
The radical B of compoun~ 1' can be subject~d to subsequent
reactions, whereby the compound 1~ results. Thc nature of the
subsequent reaction depends especially on the nature of B.
For the secondary reactions 1' ~ 1" the folluwing generally
applies: reactions a) to ~) hereinafter are standard reactions
which are well-known to a person skill~d in the art and the given
paramet~rs, such as reagents, reactiorl conditions etc., are
therefore to be unders~ood to be purely illustrative.
~)
-SCN
-sc(=O)-cH3 ~ to -SH or to -S-S- ("dimers" of 1')
-S-C(=NH)-NH2
a) carried out using H~/H20
in polar solvents (e.g. EtOH, H20, etc.)
or
b) carried out using HO-/RsO- (R6 = Me, Et, t-butyl, etc.)
in polar solwnts (EtOil, H20, etc.)
T = 0-100C, e.g. about 2aoc
O B~
-SCN
SC(=O3-CH3 or-S-acyl (e.g. butyryl~
~S-C~=NH)-NI 12 to -SH
-S-SO3A
-S-S- R5
-S(O)2-R5 to -S-R5
~L~
e.g. NaBH4, LWH4, NaBH~C;N
Sn/HCI, Zn/CH3COOH, Na2S2C)3
phosphine (e.g. tributylphosphine)
as well as Na/NH3 or
H2 cat. (cat. = e.~. Pd, Pt~ Rh, etc.)
preferably in polar solvents such as H2O/EtOH, acetiG acid,
ether, MTBE, tetrahydrofuran, et~.
T = about -80C to about 1ûûC, e.g. 20C.
-SH to -S-S- (ndimer~ of 1')
using 12 or H2O2 in polar solvents (e.g. EtOH, H2O)
T= 0-100C
~) ~k~
Namely at the S-~om in the 3-position of compound 1' by
exchange of the side-chain residue bonded to this S, e.g. by the
new side-chain residue R4 or SR5 using suitable reagents; it can
be effected e.g. in accordance with
-SCN to -SR4 (1),
-SCOCH3 to -SS-{~1 6-alkyl (2~,
-SC~-NH)NH2 to -SS-heteroaryl (3), e.g. dimers of 1'
-S-SO3H
-SH to -SR4 (4~
(1) Hal-R4, e.~. CH31, Ci(CH)2COCH~ rCH2COOH, etc.,
(2) A-S-alkyl, e.~. A-SCH3,
(3) A-S-heteroaryl, e.g. 3-marcaptothiophene, furfuryl-
mercaptan, 3-mercaptofuran, etc.,
~4) HalR4.
From this compilation it will be evident that radical C of
fermula I embraees the residues defined by B and S-R.
~çbbQ~
Preferably in polar solvents, such as H2O, ethanol, ethers,
acids such as acetic acid, optionally using bases, such as the
usual hydroxides, carbonatss, bicarbonates, alkylates, acetates,
tert.amines, etc., at temperatures of about 0 to about 10C.
The working-up is preferably effected by extraction:
extracltion between water or possibly dilu~e aoid and an oryanic
solvent, such as ether, MTBF, CH2CI2, hexane, pentane, toluene,
etc., separation of the organic phases and concentration (evapor-
ation) of the organic solvent.
~C~
This is prefer~bly carried out by distillation or in a given
instance by chromatography.
The compounds I are for the mosl: part known and to some
extent flavorants which are present in nature, e.g. meat flavours.
7 ~8~72
Examples of such substances are the mercaptans and
disulphides exempli~ied in the foliowing Examples.
The following ean be men~ioned as fur~her examples:
æ ~ v ~
~S-cH3
R1 ~\ 2 i (F~/S ~II/ (F)~S~/ (F~S~SH
O O
(F)
,S~COOH (F~,S~
(F)~S~ (F)~S~
R1 R2 Rl S R2
A~yl derivativ~s
~S~ (F)~S~
æ~
S--S--CH3
R1 ~R2 ~S--S~
æ,Y~
S--S R1 Rl ~3\R2
8 æo~72
The above mono-S-compounds are accessible by the primary
reaction in accordance wi~h ~he invention.
The above disuiphides are aceessible especiaily by one of
the subsequent reactions a) to ~), whereby in this case the
substitution stands in the foreground.
Formula 1, however, also embraces in accordance with the
definition compounds 1"', namely the compounds
SCN
~¢~
R~ o R2
~...
wherein R1 and R2 signify H, CH3 or C2Hs and R1= R2 ~ H.
These compounds are ncvel intermediates for the
manufacture of flavorants.
In the case of the flavorants I the compounds which are
identical with those fcund in nature are especially preferred.
a) 2~
5.61 g of 5-hydroxyhex-3-yn-2-one [prepared according to
A. F. Thomas et al., Tet. Lst. ~Z, 505, ~1986)3 in 50 ml of methyl-
ene chloride are add~d dropwise while stirring wi~hin 15 min. to
a mixture of 11.42g of thioacetic acid in 50 ml of methylene
chloricle and 100 ml of 2N sulphuric acid. After leaving to stand
a~ room temperature for 2 hours the mixture is heated to 40C
and stirred at 40C for a further 4 hrs. The reaction mixture is
9 ~9~ 72
poured into 100 ml of H2C) and extracted 2 x with 100 ml of
methylene ohloriEle. The or~anic phases, dried over MgS04, are
ooncentrated and fractionally distilled in a high vacuum
(65C/0.2 mbar). There are obtained 5.7g (67% of theory) of a
yellow liquid. NMP~ (CDC13) 2.22 pprn ~s/~H); 2.26 (s/31!); 2.38
(s/3H); 5.89 ~s/1 H).
b) ~
2 g of th~ thioacetate ob~ained above arc dissolved in
25 ml of methanol and treated with Z50 mg of sodium oarbonate.
After stirring at 50C for 3 hours the reaction mixture is
partitioned between water and ether and the organio phase is
dried over rnagnssium sulphate and concerltrated. The 1.3 g o
crude product obtaincd are distill0d at 100C/0.13 rnbar.
NMR (CDCI~) 2.09 ppm (s/6H); 2.24 (s/6H); 5.97 (s/2H).
~m~l~, .
a) ~ibl~
The procedure described in Exarnple 1a is followed, but 4-
hydroxy-2-pen~ynal diethyl acetal [prepared according tc
R.G.Jones and M.J.Mann, J.Am.Chem.Soc. 7~, 4048, (1953)] is used
in place o~ 5-hydroxyhex-3-yn-2-one. Ther~ is obtained in 12%
yield a yellow liquid (b.p. 35G/0.2 mbar~.
NMR (CDCI3): 2.3 ppm (s/3H); 2.4 (s/3H); 6.35 (d/1H); 7.4 ~d/lH).
b~ ~t ~
The thioac~ta~e ob~ained above is reacted in accordance
with Example 1b. The~e is obtained the desired product, b.p.
77C/0.4 mbar.
NMR (CDCI3) 2.1 ppm (s/6H); 6.3~ (s/2H); 7.28 (s/2H~.
209817 2
a) ~ ~,~I~YA~
1300ml of pentane are added ~o a solution of 115.3g of
sodium rhodanide in 13ûO ml of 2rl sulphurio acid. Then, 145 g
of 5-hydroxyhex-3-yn-2-one [prepared ~ccording to A.F.Thomas et
al., Tet. Let. ~Z, 505, ~19~6)1 are added dropwise thereto within
120 minutes while s~irring. The phases are separated and the
aqueous phaso is ~xtracted 2 x with 1000 ml of pentane. The
combined or~anic phases ara washed with 250 ml of saturat~d
NaCI solu~ion, dried over MgSO~" conoentrated and fractionally
distilied in a high vacuum (53C/0.14 mbar). Th~re are obtained
94.8 g (48% of theory~ of a yellow liquid.
NMR (CDCI3): 2.22 ppm (s/3H); 2.38 (s/3H); 6.06 (s/lH).
7.6 g of sodium hydroxide are dissolved in 200 ml of H2O
and 14.6g of the thiocyanate obtained above arc addod dropwise
within 30 minu~es while s~irring. After 90 rninutes at room
temperatlJre the reaction mix~ure is partitioned be~ween water
and pentane, the organic phase is dried over MgSO~, concentrated
and distilled in a high vacuum at 100C/0.13 mbar. There are
obtained 9.2g (76% yield) of a yellow liquid.
NMR spectrum see Example lb.
3-(2,5-Dime~hylfuryl)-thiocyanate (prepared according ~o
Example 3a) in 50 ml of m~hanol is added dropwise while
stirring within 40 minutes to a solution of 13.7 g of sodium
hydroxide and 35.6 g of methyl iodids in methanol. Then, the
reaction mixture is poured into 500 ml of H2O and extracted
1 1 2 ~ 7 2
3 x with 700 ml of methyl ter~-bu~yl ether. The organic phases,
dried over MgSO4, are ooncentrat~d and distilled in a wat~r-jet
vaouum at 71C/19mbar. There are ~hus obtained 22.89 (70% of
theory) of a olear oil.
NMR(CC)C13); 2.22. ppm (s/3H~; 2.25 (s/311); 2.28 (s/3H); 5.94
(s/1 H).
~.qm~
2~b~ (an ~specially preferrcd compound)
126.3g of potassium carbonate and 12.7 9 of sodium
dithionite are dissolved irl ~00 ml of water, then 200 ml of 2-
mercaptoethanol and 8.5 ~ of 3-(2,5-dimethylfuryl)-thiocyanate
(prepared according to Example 3a) are added dropwisa in suoces-
sion while stirring. After standing at room temperature for
30 min. the reaction mixture is brought to pH 2 slow!y with
200 ml of conc. hydrochloric acid and the aqueous phase is
extraoted 3 x with 300 ml of pentane. The organic phases, dried
over MgSO4, ar~ conc~ntrated and distilled on a waterjet vacuum
at 80C/13 mbar. There are obtained 4.5 g (57% yield) of a red
liquid.
NMR (CDCI3): 2,22 ppm (s/3H); 2,27 (s/3H); 2,62 (d/lH); 5,~8
(sJ1 H).
~a~
~an especially preferred oompound)
a) ~l~h~f~
The procedure described in Exarnple 3a is followed, but 4-
hydroxy-2-pentynal diethyl acetal [prepared according to
R.G.Jones and M.J.Mann, J.Am.C:hem.Soc. 7~, 4048 (1953)] is used
in place of S-hydroxyhex-3-yn-2-one. A~ter fractional distil-
lation in a high vacuum at 51C/0.6 mbar 3-(2-methylfuryi)-
~hiooyanat0 is obtain~d in 80% yield.
NMR (C[)CI3): ~.42 ppm ~s/3H); 6.5 (cV1H); 7.37 (d/1H).
12 ~9~72
b) ~e~h :~lb;el
0.6 9 of sodium borohydride is addetl to a solution of 2.1 g
of 3-(2-methylfuryl)-thiocyanate in 20 ml of methanol and the
mixture is heat~d to reflux ~emperature. After stirrin~ under
reflux for 3 hours a further 0.6 9 of sodium borohydride is added
and the mixture is stirred for a furth~r 15 minutes. Then, the
reaction mixture is poured into 50 ml of water and extracted
3 x with 50 ml of methyi tert-bu~yl ether. The oombined
organic phases are dried over MgSO4 an~l ooncentrated. The 1.6 g
of crude produc~ obtained are distilled at 140C/normal pressure.
NMR ~CDC13) 2.33 ppm (s/3H~; 2.66 (d/1H); 6.3 (d/1H); 7.25 (d/lH).
~m~
MethYl 2~b~L~I~
3-(2-Methylfuryl)thiocyanate (prepared accordin~ to
Example 6a~ is added dropwise while stirrin~ within 25 minutes
to a solution of 4.3 ~ of sodium methylmercaptide in 10û ml of
water. ~ter stirring at room temperclture for 30 minutes
100 ml of pentane are added and the aqueous phase is separated
from the organic phas~. Tha aqueous phase is extracted ~ x with
100 mi of pentane. The combined organic phases are dried over
M~SO4, concentrat~d and fractionally distilled in a high vacuum
(37C 0.48 mbar~. The desired product is obtained.
NMR (CDC13); 2.4 ppm (s/3H); 2.45 (s/3H~; 6.44 (d/111~; 7.28
(d/1 H).
6.2 ml of triethylamine and 4.02 g of n-butylmercaptan are
simultaneously added dropwise while stirring to a solution of 5g
of S-hydroxyhex-3-yn-2-ona ~preparad accordin~ to A.F.Thomas et
al., Tet. Let. 27, 505, (1986~3 in 40 rnl of methyl tert-butyl ether
(MTBE). After 60 minutes at room temperature 70 ml of 5N
1 3 ~98172
sulphuric acid are added and the mixture is s~irred for a further
6û minutes. Then, the phases are separated, tha aqueous phase is
extracted with 2 x 50 ml of MTBE and the or~anic phase is
washed in succession wi~h water, satura~0d NaHCC)3 solution and
saturat~d NaCI solu~ion. The or~anic phases, dried over MgSO4,
are concentrated and fractionally distilled in a high vacuum
(63C/0.25 mbar). There are ob~ained 6.34 ~ (77/O yield) of the
desired product.
I\MR (CDCi3) 0.88 ppm (V3H); 1.46 (multipleV4H); 2.22 (s/3H);
2.28 (s/3H); 2.58 ~V2H); 5.6 (s/lH).
~m
~ .
The procedure described in Example 8 is followed, but
methylmercaptan is us~d in piace of n-butylmercaptan. After
fractional distillation in a water-jet vacuum (58C/22 mbar)
there is obtained a clear oil in 65% yield. Spec~ra: see Example 4.
~me~
The same product as desGribed in Example 9 is also obtained
when 5-hydroxyhex-3-yn-2-one is added dropwise to a mixture of
sodium methanethiolate in water and rnethyl tert-butyl ether and
~hereupon, as in Example 8, the mixture is treated with sulphuric
acid and worked-up.
~m~le 1~
5 ~ of S-hydroxyhex-3-yn-2-onc in 25 ml of ether are
added ~ropwise while stirring to a mixture of 6.6 ~ of sodium
hydrogen sulphide monohydrate in 20 ml of buffer pH 9 (borax/
boric acid) and 30 rnl of ether. After stirrin~ for 3 hours the
14 ~9~172
mixture is acidified and stirred for one hour. The organic phase
is separated, ooncen~ra~ed and chromatogra,~hed in h~xane over
silica gel. The eonGentrated top fractions give pure product
which is identieal with ~he product from Example 1a.
